Topical corticosteroids are used to treat many acute and chronic dermatologic and mucosal disorders, especially those in which pruritus or inflammation is present. Many such conditions, such as eczema, psoriasis, and chronic dermatitis, such as hand dermatitis, are chronic conditions that require long-term therapy.
Corticosteroids for topical application are grouped within a classification system into seven classes based on potency. Topical potency of a corticosteroid is determined by a standard test, referred to as a VasoConstrictor Assay (VCA). The VCA test is described in Dow et al, U.S. Pat. No. 7,300,669, incorporated herein by reference.
Table 1 shows the classification of topical corticosteroids based on potency as determined by the VCA test.
TABLE 1Potency Chart of Topical CorticosteroidsClass 1-SuperpotentClobetasol propionate 0.05%Betamethasone dipropionate ointment 0.05%Halobetasol propionate 0.05%Fluocinonide 0.1%Diflorasone diacetate ointment 0.05% (Psorcon ®)Class 2-PotentBetamethasone dipropionate cream 0.05%Mometasone furoate ointment 0.1%Diflorasone diacetate cream 0.05% (Psorcon ®)Diflorasone diacetate ointment 0.05% (Florone ®)Halcinonide 0.1%Desoximetasone cream/ointment 0.25%Desoximetasone gel 0.05%Fluocinonide cream/gel/ointment 0.05% (Lidex ®)Amcinonide 0.1%Budesonide 0.025%Beclomethasone 0.025%Class 3-Upper Mid-strengthFluticasone propionate ointment 0.005%Fluocinonide cream 0.05% (Lidex-E ®)Betamethasone valerate 0.12%Desoximetasone cream 0.05%Class 4-Mid-strengthFlurandrenolide ointment 0.05%Mometasone furoate cream 0.1%Triamcinolone acetonide 0.1%Fluocinolone acetonide 0.03%Hydrocortisone valerate 0.2%Class 5-Lower Mid-strengthFluocinolone acetonide shampoo 0.01%Flurandrenolide cream/lotion/tape 0.05%Fluticasone propionate cream/lotion 0.05%Prednicarbate cream 0.1%Desonide lotion 0.05%Hydrocortisone butyrate cream/lotion/ointment/solution 0.1% (Locoid ®)Hydrocortisone probutate cream 0.1% (Pander ®)Fluocinolone acetonide cream 0.03%/0.01% (Synalar ®)Hydrocortisone valerate cream 0.2%Class 6-MildAlclometasone dipropionate 0.05%Fluocinolone acetonide oil 0.01%Desonide gel 0.05%Fluocinonide cream/solution 0.01%Desonide foam 0.05%Class 7-Least PotentHydrocortisone lotion 0.5%/1%Hydrocortisone cream/spray/ointment 1%Hydrocortisone cream lotion 1%/2.5%
The most potent group of corticosteroids, determined on the basis of the VCA, is denoted Class 1 superpotent corticosteroids. In this specification, when a concentration is indicated with a particular corticosteroid, for example as an ester, an acetonide, a free alcohol, or a diester, the corticosteroid is stated as a particular form of the corticosteroid. When no concentration is indicated with a corticosteroid, or when a concentration refers to the corticosteroid in more than one form, such as an ester, an acetonide, a free alcohol, or a diester, the corticosteroid is stated without reference to the particular form. All known preparations of clobetasol propionate and halobetasol propionate, all of which are at a concentration of 0.05% w/w, are classed as superpotent corticosteroids. Other corticosteroids classified as superpotent are certain preparations of betamethasone dipropionate at a concentration of 0.05%, diflorasone diacetate at a concentration of 0.05%, and fluocinonide at a concentration of 0.1%. The next most potent group of corticosteroids is denoted Class 2 potent corticosteroids. This group includes mometasone furoate at a concentration of 0.1%, halcinonide, diflorasone diacetate, desoximetasone, fluocinonide at a concentration of 0.05%, and cream formulations of betamethasone at a concentration of 0.05%.
The superpotent corticosteroids are utilized for skin conditions that are not satisfactorily responsive to lower potency corticosteroids. Such conditions include psoriasis and certain severe types of eczema. Unfortunately, because of the high potency of the Class 1 corticosteroids, which correlates with a high incidence and severity of systemic side effects, including hypothalamic-pituitary-adrenal (HPA) axis suppression, topical treatment with superpotent corticosteroids is generally limited in duration to 2 weeks. Such side effects may also occur with treatment with Class 2 potent corticosteroids. Additionally, the occurrence of local adverse reactions limits the duration of use of superpotent and potent corticosteroids with respect to treatment of chronic or recurrent skin diseases.
Chronic skin conditions, such as psoriasis, however often require long periods of treatment, greater than 2 weeks, to manage such conditions. Therefore, it would be desirable to have a superpotent corticosteroid formulation with a reduced incidence and/or severity of systemic side effects so that therapy can be continued for durations longer than 2 weeks.
Dow, U.S. Patent Publication 2006/0239929 discloses a spray formulation containing 0.05% clobetasol that was shown to be efficacious and to have few serious side effects when administered for periods of 4 weeks. The disclosure of Dow, however, was limited to a spray formulation and the prosecution history of this application shows that prior art formulations of 0.05% clobetasol are associated with high frequencies of serious systemic side effects, including hypothalamic-pituitary-adrenal axis suppression when applied for a period of 2 weeks.
Because of the tendency of all superpotent corticosteroids to cause serious systemic effects, the FDA (Food and Drug Administration) requires that the prescribing information for currently marketed topical compositions of superpotent corticosteroids, such as clobetasol and halobetasol, except for a particular spray formulation of clobetasol, carry the warning that treatment beyond 2 consecutive weeks is not recommended, and the total dosage should not exceed 50 g of the composition per week. Regarding the clobetasol spray formulation, the prescribing information states that treatment should be limited to 4 weeks and that treatment beyond 2 weeks should be limited to localized lesions of moderate to severe plaque psoriasis that have not sufficiently improved after two weeks. Regarding potent corticosteroids, the FDA does not require the prescribing information to carry this warning, but does caution the physician to be aware of and to monitor for the occurrence of HPA axis suppression.
Busse, U.S. Pat. No. 4,370,322, concerns the problem of systemic side effects due to topical application of high-potency corticosteroids. Busse discloses a topical pharmaceutical composition containing a high-potency corticosteroid and an oil phase that contains a low viscosity oily solvent, wherein the concentration of the liquid oil phase is at least three times that which is required to completely solubilize the corticosteroid. Busse discloses that, when the solvent-containing oil phase is present in such high concentrations relative to the corticosteroid, the systemic absorption of the corticosteroid is reduced but the local, desirable effects of the corticosteroid are maintained. Busse further disclose that this discovery permits the application of the same amount of steroid to achieve the same local anti-inflammatory effect while reducing unwanted systemic effects.
Parab, U.S. Pat. No. 5,326,566, in contrast to the disclosure of Busse which discloses that a high concentration oily phase will decrease systemic absorption of a corticosteroid when applied to the skin, discloses that, when a formulation contains a skin penetration enhancing amount of dibutyl adipate or a mixture of dibutyl adipate and isopropyl myristate at a concentration that is sufficient to dissolve the corticosteroid in the formulation but which is less than 1.5 times that which is required to dissolve the corticosteroid, the penetration of the corticosteroid through skin and into the systemic circulation is increased rather than decreased. Thus, Parab discloses that formulations containing a corticosteroid and an oily phase containing dibutyl adipate, alone or in combination with isopropyl myristate, at a concentration between 1 and 1.5 times that required to dissolve the corticosteroid are useful for increasing the systemic absorption of a topically applied corticosteroid.